A study of determinants of direction of kinesins

学位の種別: 課程博士審査委員会委員 : （主査）東京大学准教授 矢島 潤一郎, 東京大学教授 豊島 陽子, 東京大学准教授 大杉 美穂, 東京大学准教授 佐藤 健, 東京大学准教授 若杉 桂輔University of Tokyo(東京大学

Motor generated torque drives coupled yawing and orbital rotations of kinesin coated gold nanorods

Kinesin motor domains generate impulses of force and movement that have both translational and rotational (torque) components. Here, we ask how the torque component influences function in cargo-attached teams of weakly processive kinesins. Using an assay in which kinesin-coated gold nanorods (kinesin-GNRs) translocate on suspended microtubules, we show that for both single-headed KIF1A and dimeric ZEN-4, the intensities of polarized light scattered by the kinesin-GNRs in two orthogonal directions periodically oscillate as the GNRs crawl towards microtubule plus ends, indicating that translocating kinesin-GNRs unidirectionally rotate about their short (yaw) axes whilst following an overall left-handed helical orbit around the microtubule axis. For orientations of the GNR that generate a signal, the period of this short axis rotation corresponds to two periods of the overall helical trajectory. Torque force thus drives both rolling and yawing of near-spherical cargoes carrying rigidly-attached weakly processive kinesins, with possible relevance to intracellular transport

CYK4 relaxes the bias in the off-axis motion by MKLP1 kinesin-6

Centralspindlin, a complex of the MKLP1 kinesin-6 and CYK4 GAP subunits, plays key roles in metazoan cytokinesis. CYK4-binding to the long neck region of MKLP1 restricts the configuration of the two MKLP1 motor domains in the centralspindlin. However, it is unclear how the CYK4-binding modulates the interaction of MKLP1 with a microtubule. Here, we performed three-dimensional nanometry of a microbead coated with multiple MKLP1 molecules on a freely suspended microtubule. We found that beads driven by dimeric MKLP1 exhibited persistently left-handed helical trajectories around the microtubule axis, indicating torque generation. By contrast, centralspindlin, like monomeric MKLP1, showed similarly left-handed but less persistent helical movement with occasional rightward movements. Analysis of the fluctuating helical movement indicated that the MKLP1 stochastically makes off-axis motions biased towards the protofilament on the left. CYK4-binding to the neck domains in MKLP1 enables more flexible off-axis motion of centralspindlin, which would help to avoid obstacles along crowded spindle microtubules

Neutron Electric Dipole Moment under Non-Universal Soft SUSY Breaking Terms

金沢大学理工研究域数物科学系The electric dipole moment of the neutron (EDMN) is re·examined in the framework of non-universal soft supersymmetry breaking. We review some features of the relation between the EDMN and non-universal soft supersymmetry breaking terms. It is shown that the constraints on the soft scalar masses and soft CP phases have a rather strong dependence on the non·universality of soft breaking terms. We also show that the soft CP phase if>s which has no natural suppressionmechanism may not contribute significantly to the EDMN in a certain parameter region where the radiative symmetry breaking occurs successfully. If this is the case, if>s may not need to be so small

Passive smoking and chronic obstructive pulmonary disease mortality: findings from the Japan collaborative cohort study.

OBJECTIVES:To elucidate the association between passive smoking at home and chronic obstructive pulmonary disease (COPD) mortality via a large-scale nationwide cohort study in Japan.METHODS:Never smokers (n = 34,604) aged 40-79 years at baseline (1988-1990; 4884 men, 29,720 women) were included in the analysis. Passive smoking at home was measured based on self-reported frequency of weekly exposure to passive smoking at home. An inverse probability of treatment-weighted competing risk model was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for COPD mortality.RESULTS:During a median follow-up of 16.4 years, 33 participants (10 men, 23 women) died of COPD. The HR for participants exposed to passive smoking at home ≤4 days per week or those who had almost daily exposure to passive smoking at home had a significantly increased risk of COPD mortality (HR 2.40, 95% CI 1.39-4.15, HR 2.88, 95% CI 1.68-4.93, respectively)

Association between markers of arterial stiffness and atrial fibrillation in the Circulatory Risk in Communities Study (CIRCS).

Background and aims:Limited evidence is available on the association between markers of arterial stiffness and the prevalence of atrial fibrillation among Asian populations. Therefore, we examined those associations in the Japanese population.Methods:We conducted a cross-sectional population-based study of 4264 men and women aged 40-79 years. The augmentation index (AI), a marker of arterial stiffness, was calculated as the ratio of central pulse pressure/brachial pulse pressure, where the AI and central aortic pressure were measured by an automated tonometer: the HEM-9000AI device (Omron Healthcare co., Kyoto, Japan). Atrial fibrillation was estimated by the Minnesota codes using resting electrocardiograph (ECG).Results:The prevalence of atrial fibrillation and total arrhythmia were higher with larger AI values. These associations did not change after adjustment for known cardiovascular risk factors. The multivariable odd ratios (95% confidence intervals) in the highest versus lowest tertiles of AI were 3.4 (1.4-8.6, p for trend = 0.008) for atrial fibrillation and 1.8 (1.2-2.7, p for trend = 0.004) for total arrhythmia. There was no association of central or brachial pulse pressure levels with the prevalence of atrial fibrillation or total arrhythmia.ConclusionAI values, but not brachial or central pulse pressures, were positively associated with the prevalence of atrial fibrillation and total arrhythmia, independent of cardiovascular risk factors

Pillar[6]arene acts as a biosensor for quantitative detection of a vitamin metabolite in crude biological samples

ビタミン代謝物を迅速定量できる超分子バイオセンサーを開発. 京都大学プレスリリース. 2020-12-09.Metabolic syndrome is associated with obesity, hypertension, and dyslipidemia, and increased cardiovascular risk. Therefore, quick and accurate measurements of specific metabolites are critical for diagnosis; however, detection methods are limited. Here we describe the synthesis of pillar[n]arenes to target 1-methylnicotinamide (1-MNA), which is one metabolite of vitamin B3 (nicotinamide) produced by the cancer-associated nicotinamide N-methyltransferase (NNMT). We found that water-soluble pillar[5]arene (P5A) forms host–guest complexes with both 1-MNA and nicotinamide, and water-soluble pillar[6]arene (P6A) selectively binds to 1-MNA at the micromolar level. P6A can be used as a “turn-off sensor” by photoinduced electron transfer (detection limit is 4.38 × 10−6 M). In our cell-free reaction, P6A is used to quantitatively monitor the activity of NNMT. Moreover, studies using NNMT-deficient mice reveal that P6A exclusively binds to 1-MNA in crude urinary samples. Our findings demonstrate that P6A can be used as a biosensor to quantify 1-MNA in crude biological samples

Dietary fiber intake and risk of incident disabling dementia: the Circulatory Risk in Communities Study

OBJECTIVES: It has been hypothesized that dietary fiber intake has a beneficial impact on prevention of dementia, but the epidemiological evidence is scant. We sought to examine whether dietary fiber intake is inversely associated with risk of dementia requiring care under the national insurance (disabling dementia). METHODS: The study setting was the Circulatory Risk in Communities Study, involving 3739 Japanese individuals aged 40-64 years at the dietary surveys (1985-99). Dietary fiber intake was estimated using the 24-hour dietary recall method. Incident disabling dementia was followed up from 1999 through 2020. Disabling dementia was further classified into that with or without a history of stroke. Hazard ratios of disabling dementia according to quartiles of total, soluble, and insoluble fiber intake were calculated using the Cox proportional hazards model. RESULTS: During a median 19.7-year follow-up, a total of 670 cases of disabling dementia developed. Dietary fiber intake was inversely associated with risk of dementia: the multivariate hazards ratios (95% confidence intervals) were 0.83 (0.67-1.04), 0.81 (0.65-1.02), and 0.74 (0.57-0.96) for individuals with the second, third, and highest quartiles of dietary fiber intake, respectively, as compared with the lowest quartile (P for trend = 0.03). The inverse association was more evident for soluble fiber intake and was confined to dementia without a history of stroke. As for fiber-containing foods, potatoes, but not vegetables or fruits, showed a similar association. CONCLUSIONS: Dietary fiber intake, especially soluble fiber, was inversely associated with risk of disabling dementia in a general Japanese population

Association of cigarette smoking with radial augmentation index: the Circulatory Risk in Communities Study (CIRCS)

This study aimed to assess the association of cigarette smoking with radial augmentation index among the Asian general population. We conducted a cross-sectional population-based study including 1593 men and 2671 women aged 40–79 years. Smoking status was ascertained through interviews, and the number of pack-years was calculated. The radial augmentation index was defined as the ratio of central pulse pressure to brachial pulse pressure, as measured using an automated tonometer: the HEM-9000AI (Omron Healthcare co., Kyoto, Japan). There was a higher prevalence of an increased radial augmentation index among current male smokers who smoked ≥ 30 cigarettes/day and all female smokers than among never smokers. After adjusting for known risk factors of atherosclerosis, the multivariable odds ratio (OR) [95% confidence interval (CI)] for a high radial augmentation index for current male smokers who smoked ≥30 cigarettes/day compared with never smokers was 1.9 (1.1–3.4). The multivariable OR (95% CI) for a high radial augmentation index for former female smokers and current female smokers compared with never smokers was 1.8 (1.2–2.7) and 2.5 (1.6–3.9), respectively. Moreover, smoking pack-years was positively associated with a high radial augmentation index in both sexes. There were no relationship between smoking status and high central or brachial pulse pressures among subjects of either sex. In conclusion, cigarette smoking and cumulative smoking exposure were positively associated with an increased radial augmentation index in men who smoked heavily and in women